The reaction of 14-hydroxy dihydromorphinone, Naloxon and Naltrexon with hydrazine was reported first time in 1980 (G. W. Pasternak; E. F. Hahn: J. Med. Chem. 23 674 (1980)). When the condensation products thus formed, the hydrazones were submitted to pharmacological examinations, it turned out that the original activity A 3690-123-HB1 of the starting molecules (analgetic or morphine-antagonistic activity) is retained, however, the duration of the effect of the compounds significantly increased.
It was established in the course of the further examinations that the activity of the hydrazone derivatives can be attributed to the formation of ketazines [E. F. Hahn, M. Carroll-Buatti; G. Pasternak: J. Neuroscience 2 (5) 572 (1982); E. F. Hahn, G. Pasternak: Life Sci. 31 1385 (1982); S. Saletta, G. S. F. Ling, L. Wolfin, G. W. Pasternak: Life Sci. 31 1389 (1982)]. The authentic ketazines selectively link to opiate receptors in vitro 20-40 times better, than the corresponding hydrazone analogues.
When the .sup.13 C-NMR analysis of the hydrazones was carried out, it was found, that they are the mixture of syn and anti isomers, wherein the sterically less crowded anti isomer is the dominant [V. M. Kolb, J. R. Gober: Life Sci. 33 Suppl. I 419 (1982); V. M. Kolb; D. H. Hua: J. Org. Chem. 49 3824 (1984)]. According the above authors only the anti isomer product was formed in the reaction of oxymorphone, Naloxon, and Naltrexon with N,N-dimethyl hydrazine.
Hungarian researchers prepared Naloxone phenylhydrazine [Szucs M., Toth G., Benyhe S.: MTA Biol. Oszt. Kozl. 25 655 (1982)], while Chinese authors described the hydrazones and N,N-dimethyl hydrazones of 14-hydroxy morphinone and 14-hydroxy codeinone [M. Liu, C. Chi, Y. Gvo, C. Zhu: Yaoxue Xuebao 18 475 (1983); C. A. 100 (15) 121411b (1984)].
As the hydrazone derivatives are very interesting from pharmacological point of view, therefore our experiments were extended to further morphine-skeletoned ketons (dihydrocodeinone, dihydromorphinone, dihydrotebainone, codeinone, 14-hydroxy codeinone, 14-hydroxy dihydrocodeinone).
In the prior art the hydrazone derivative of more morphine-skeletoned ketone has been described. They were prepared mainly for analytical purposes, as the semicarbazones, phenylhydrazones, 2,4-dinitro phenylhydrazones can be well crystallized.
The preparation of the hydrazone of 14-hydroxy codeinone and 14-hydroxy dihydrocodeinone was reported even in 1924 [E. Speyer, K. Sarre: Ber. 57 1422 (1924)].